Prudent Use of Antibiotics

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Article | 08.11.2020

As veterinary practitioners, we constantly aim to improve and safeguard the health status of our farms through good management and biosecurity. Despite these preventative measures, curative intervention with antimicrobials is still required. The educational background and professional experience of the veterinarian enables them to choose the right antimicrobial for the diagnosed causative pathogen.

Along with the choice of treatment, the correct application is of major importance to ensure efficacy. Prudent use of antimicrobials does not only mean reducing their use, but also choosing the right product and administering it in an appropriate manner.

The choice of the right anticmicrobial depends on the known or suspected sensitivity of the infectious agent. The suspected sensitivity can be based upon the experience of the veterinarian, farm history and surveys of the antimicrobial sensitivity against pathogens in certain areas. This might help to start-up an empiric treatment before laboratory microbiological reports are available because treatment should not be delayed because of the seriousness of the disease and welfare implications. 

Often, antimicrobial susceptibility testing is carried out to determine which antibiotc the suspected causative pathogen is sensitive to. Testing for antibiotic sensitivity is often done by the Kirby-Bauer method, or a so-called antibiogram. With this method, small discs containing antibiotics are placed onto a plate on which bacteria are growing. If the bacteria are sensitive to the antibiotic, a clear ring or zone of inhibition is seen around the disc indicating poor growth of the pathogen (Figure 1). Other methods for testing antimicrobial susceptibility include, for example, Minimum Inhibitory Concentration (MIC) test-strips (Figure 2), agar and broth dilution methods for MIC determination. 

Figure 1. Antibiogram: agar plate with antibiotic discs. Bacteria are not able to grow around antibiotics to which they are sensitive
Figure 2. Huvepharma MIC test-strips: MIC value can easily be determined

Crucial, but difficult for all susceptibility testing is the isolation (sampling and culturing) of the relevant bacteria. This difficulty, and the lack of clinical breakpoints in animal health explain why susceptibility testing can only give an indication of the clinical outcome. 

As well as the susceptibility of the pathogens, the antimicrobial should also reach the site of infection. This is determined by the pharmacokinetic characteristics of the product. Tilmovet® is ionized. Ionized molecules cannot pass through lipid barriers anymore and consequently the molecule is trapped. This phenomenon is called ion-trapping and explains the high concentrations and accumulation of Tilmovet® in phagocytes (acidic lysosomes) and in tissue compartments with a low pH such as the lung (Table 1). 

Table 1. Concentration of tilmicosin in lung and plasma after 5 days treatment with Tilmovet® at 16 mg/kg bodyweight (Karanikolova et al., 2014)

Other antimicrobials such as paromomycin (Parofor®, an aminoglycoside registered by Huvepharma) are hydrophilic, meaning they dissolve well in water). They cannot pass through lipid barriers and consequently their uptake in the intestine is very limited. Most hydrophilic antimicrobials are therefore unsuitable for systemic treatment via oral administration. However, after single oral administration of 50 mg paromomycin/kg bodyweight, concentrations of >5000 µg/g were found in the intestinal lumen (internal data). The fact that Parofor® intensively concentrates in the intestinal lumen makes it a good option for the treatment of enteritis caused by pathogens sensitive to paromomycin. 

Sometimes, the use of more than one antibiotic may be justified, based on their synergistic effect in vitro. The combination of Vetmulin® / Rodotium® and Apravet® might be justified to treat and eradicate Brachyspira hyodysenteriae. Adding 4 µg/ml apramycin (Apravet®) to tiamulin (Vetmulin® / Rodotium®) increased the number of susceptible strains in vitro. The synergistic effect of Apravet® and Vetmulin® / Rodotium® has also been observed in the field (Table 2). 

Table 2. Susceptibility of Brachyspirae hyodysenteriae against a combination of Vetmulin® / Rodotium® (tiamulin) and Apravet® (apramycin; Vyt et al., 2014)

After choosing the antimicrobial, correct administration is also of importance. Dosing should be done in grams per kilogram of live body weight, independent of the application form. By doing so, underdosing will be avoided by taking account of the changing ratio between bodyweight and water intake. This can easily be done with Huvepharma's dose calculator, freely available for iPhone, Android and Blackberry mobile devices (Figure 3). 

Figure 3. Huvepharma's dose calculator app

The dosage regimen is also of importance. The daily dose can be administered continuously or as a pulse. For concentration-dependent antibiotics, such as aminoglycosides, a high concentration (Cmax) several times higher than the MIC of the targeted pathogen at the site of infection will result in a faster and better effect (Table 3). The most important parameter for these antimicrobials is the low Cmax/MIC. Consequently, pulse medication will work better for these types of antimicrobials. 

Table 3. Classification of antibiotics based on their ideal dosing regimen

For time-dependent antimicrobials, such as the macrolides, efficacy depends on the period during which the bacteria are exposed to the antimicrobial at a concentration just above the MIC (T>MIC). The most important parameter is the duration of time in which the concentration is higher than the MIC (T>MIC) at the site of infection. Better efficacy can be expected if these antimicrobials are provided continuously (Table 3). 

Other antibiotics, such as tetracyclines have mixed properties: they are time-dependent and concentration dependent. The ideal dosing regimen for these antibiotics maximizes the amount of drug received (Table 3). Therefore, the 24-hour Area Under the Curve (AUC/MIC) ratio is the parameter that correlates with efficacy (Figure 4). 

Figure 4. Two types of antibiotics with an ideal PK profile regarding efficacy

The formulation of the veterinary medicine can also influence the clinical outcome of an antimicrobial treatment. Stability, solubility and bioavailability of the active can be optimized by the choice of excipients and the manufacturing method. For water-soluble veterinary medicines for example, there may be a loss of activity and precipitation of the active after dissolving in the drinking water (Figure 5). This will logically affect the effectiveness of the therapy. 

Figure 5. Precipitation: an example of a water-soluble veterinary medicine unsuitable for use with a proportioner

In conclusion, we need a holistic approach to medicine use, and by that we mean responsible prescribing and responsible use of all medicines including antimicrobials. The prescribers and users of veterinary medicines should operate according to the principle "as little as possible but as much as necessary".

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